CN101903390A

CN101903390A - Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof

Info

Publication number: CN101903390A
Application number: CN2008801213953A
Authority: CN
Inventors: P·R·帕迪; B·伊蕾妮; S·波拉瓦拉普; S·帕达玛塔; K·内雷拉; V·A·拉玛萨米; R·R·万噶拉
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2007-12-20
Filing date: 2008-12-18
Publication date: 2010-12-01
Also published as: US20100274017A1; JP2011507890A; US8969558B2; WO2009085990A3; CA2707790C; IL206500A0; US20130035486A1; IL206500A; WO2009085990A2; US8309724B2; CA2707790A1; EP2679590A1; EP2220093A2; EP2599781A1; US20140128607A1; EP2220093A4; KR20100101073A

Abstract

There is provided salts and polymorphs of sitagliptin, processes for the preparation thereof, and pharmaceutical compositions comprising the same.

Description

The method for preparing sitagliptin and pharmacy acceptable salt thereof

Foreword

The application relates to sitagliptin (sitagliptin), its salt and its polymorphic form, and the method for preparing sitagliptin, its salt and its polymorphic form.

Sitagliptin is (R)-7-(1-oxo-3 ((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2, and 4-triazolo [4,3-a] pyrazine is represented with structural formula II.

Sitagliptin is dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitors of Orally active, and its deactivation by the incretin hormone that slows down improves the patient's who suffers from type ii diabetes glycemic control.Sitagliptin can be used as monotherapy, unites use as the auxiliary of diet and exercise or with N1,N1-Dimethylbiguanide or PPAR gamma agonist (for example thiazolidinediones).

United States Patent (USP) 6,699,871 have described class beta-amino tetrahydrochysene triazolo [4, a 3-a] pyrazine, and they are effective inhibitor of DPP-IV and therefore are used for the treatment of type ii diabetes.United States Patent (USP) 6,699 discloses sitagliptin in 871 particularly.The pharmacy acceptable salt of this compound is included in United States Patent (USP) 6,699 prevailingly, in 871 the scope.It also discloses the method for preparing sitagliptin and related compound.

International application published WO 2004/085661 discloses the method for preparing sitagliptin, and wherein, to form intermediate, this intermediate provides required enantiomorph (being sitagliptin) to the S-phenylglycinamide subsequently as chiral auxiliary(reagent).

International application published WO2004/087650 discloses another kind of method, and wherein, enantioselectivity ground synthesizes the shielded 3-of N-((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyric acid, with condensation of pyrazine intermediate and deprotection, so that sitagliptin to be provided.

United States Patent (USP) 7,326,708 disclose dihydrogen phosphate of sitagliptin and preparation method thereof.

International application published WO 2004/085378 discloses the method for preparing sitagliptin, wherein, and by using rhodium metal and chiral ferrocene base diphosphine reduction sitagliptin intermediate.

Though prior art has been reported several methods that prepare sitagliptin; but; they have one or more shortcomings, use hazardous agents (as platinum oxide, rhodium catalyst etc.), expensive reagent (such as chloropyrazine, dichloropyrazine etc.) and a large amount of protection and deprotection steps such as relating to.Therefore, just needing simple, economical and the industrial feasible method for preparing sitagliptin and pharmacy acceptable salt thereof.

The crystal salt of sitagliptin is known.The various crystal salt of international application published WO 2005/072530 open sitagliptin, international application published WO 2006/033848 has described the amorphous form of the dihydrogen phosphate of sitagliptin.International application published WO 2005/020920 discloses the two kinds of anhydrous crystalline forms (being form I and form III) and the desolvated dehydration crystalline form II of the dihydrogen phosphate of sitagliptin.International application published WO 2005/030127 discloses the dehydration crystalline form IV of the dihydrogen phosphate of sitagliptin.International application published WO 2005/072530 discloses crystalline hydrochloride, benzene sulfonate, tosilate, 10-camsilate and the tartrate of sitagliptin.International application published WO 2007/035198 discloses the dodecyl sulfate of sitagliptin.

Still require further improvement the character of solid-state sitagliptin, such as stability, purity, flowability, steam-impermeable, solubleness and bioavailability.

Application outlined

The present invention includes the method for preparing sitagliptin, at least one in said method comprising the steps of:

(i) make 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4, the 3-a] pyrazine and first reagent react, so that 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5 to be provided, 6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine;

(ii) make 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5 with second reagent, 6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine is converted into 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine;

(iii) use the described 7-of the 3rd agent treated (1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine, so that 7-(1-oxo-3 ((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5 to be provided, 6,7,8-tetrahydrochysene-1,2, the diastereoisomeric salt of 4-triazolo [4,3-a] pyrazine;

(iv) separate described diastereoisomeric salt;

(v) use the described diastereoisomeric salt of acid or alkaline purification, so that Januvia free base to be provided; With

(vi) randomly use the described Januvia free base of acid treatment, so that the acid salt of sitagliptin to be provided.

(i) make 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine and chiral reagent reaction are with the compound of preparation formula VIII, and wherein R is C ₁-C ₄Alkyl;

(ii) the compound of formula VIII is converted into the compound of formula IX, wherein R as above defines;

(iii) use acid or alkali or catalyzer that the compound of formula VIII is transformed, so that Januvia free base to be provided;

(iv) randomly use the described Januvia free base of acid treatment, so that the acid salt of sitagliptin to be provided.

The present invention includes the anhydrous crystal sitagliptin dihydrogen phosphate (hereinafter being also referred to as form A) of formula I '.

Form A can characterize with dsc (DSC) thermogram, and from about 201 ℃, endotherm(ic)peak appears at about 205.5 ℃.

Form A can also characterize with its X-ray diffractogram, has characteristic peak at the diffraction angle 2-θ place of about 4.58,9.23,12.24,13.88,18.23,23.63,24.24 and 26.68 ± 0.2 degree.

Form A can also characterize with as shown in fig. 1 X-ray diffractogram basically.

And form A can characterize with thermogravimetric analysis (TAG) curve, and temperature is corresponding about 0.038% (0.01082mg) weight loss (as shown in Figure 3) during up to about 100 ℃.

The present invention includes the method for preparing form A, described method is included in water-content less than the step of handling Januvia free base in about 6% the aqueous isopropanol with phosphoric acid.

Except form A, the present invention also comprises vitriol, hydrobromate, mesylate, acetate, benzoate, oxalate, succinate, amygdalate, fumarate and the lactic acid salt of sitagliptin.

The present invention includes the method for the salt of preparation sitagliptin, at least one in said method comprising the steps of:

(a) provide the solution of salt in solvent of sitagliptin;

(b) salt of the described sitagliptin of separation from the solution of step (a); With

(c) crystal salt of recovery sitagliptin also randomly makes its drying.

The present invention includes the pharmaceutical composition that comprises sitagliptin of the present invention and at least a pharmaceutically acceptable vehicle.

The accompanying drawing summary

Fig. 1 illustrates X-ray powder diffraction (XRPD) figure of exsiccation form A of the dihydrogen phosphate of sitagliptin.

Fig. 2 illustrates dsc (" the DSC ") curve of exsiccation form A of the dihydrogen phosphate of sitagliptin.

Fig. 3 illustrates thermogravimetric analysis (TGA) curve of exsiccation form A of the dihydrogen phosphate of sitagliptin.

Fig. 4 explanation is according to powder x-ray diffraction (" the PXRD ") figure of the crystallization sitagliptin vitriol of embodiment 14 preparations.

Fig. 5 explanation is according to dsc (" the DSC ") curve of the crystallization sitagliptin vitriol of embodiment 14 preparations.

Fig. 6 explanation is according to thermogravimetric analysis (" the TGA ") curve of the crystallization sitagliptin vitriol of embodiment 14 preparations.

Fig. 7 explanation is according to the PXRD figure of the crystallization sitagliptin hydrobromate of embodiment 15 preparations.

Fig. 8 explanation is according to the DSC curve of the crystallization sitagliptin hydrobromate of embodiment 15 preparations.

Fig. 9 explanation is according to the TGA curve of the crystallization sitagliptin hydrobromate of embodiment 15 preparations.

Figure 10 explanation is according to the PXRD figure of the crystallization sitagliptin mesylate of embodiment 16 preparations.

Figure 11 explanation is according to the DSC curve of the crystallization sitagliptin mesylate of embodiment 16 preparations.

Figure 12 explanation is according to the TGA curve of the crystallization sitagliptin mesylate of embodiment 16 preparations.

Figure 13 explanation is according to the PXRD figure of the crystallization sitagliptin acetate of embodiment 17 preparations.

Figure 14 explanation is according to the DSC curve of the crystallization sitagliptin acetate of embodiment 17 preparations.

Figure 15 explanation is according to the TGA curve of the crystallization sitagliptin acetate of embodiment 17 preparations.

Figure 16 explanation is according to the PXRD figure of the crystallization sitagliptin benzoate of embodiment 18 preparations.

Figure 17 explanation is according to the DSC curve of the crystallization sitagliptin benzoate of embodiment 18 preparations.

Figure 18 explanation is according to the TGA curve of the crystallization sitagliptin benzoate of embodiment 18 preparations.

Figure 19 explanation is according to the PXRD figure of the crystallization sitagliptin oxalate of embodiment 19 preparations.

Figure 20 explanation is according to the DSC curve of the crystallization sitagliptin oxalate of embodiment 19 preparations.

Figure 21 explanation is according to the TGA curve of the crystallization sitagliptin oxalate of embodiment 19 preparations.

Figure 22 explanation is according to the PXRD figure of the crystallization sitagliptin succinate of embodiment 20 preparations.

Figure 23 explanation is according to the DSC curve of the crystallization sitagliptin succinate of embodiment 20 preparations.

Figure 24 explanation is according to the TGA curve of the crystallization sitagliptin succinate of embodiment 20 preparations.

Figure 25 explanation is according to the PXRD figure of the crystallization sitagliptin amygdalate of embodiment 21 preparations.

Figure 26 explanation is according to the DSC curve of the crystallization sitagliptin amygdalate of embodiment 21 preparations.

Figure 27 explanation is according to the TGA curve of the crystallization sitagliptin amygdalate of embodiment 21 preparations.

Figure 28 explanation is according to the PXRD figure of the crystallization sitagliptin fumarate of embodiment 22 preparations.

Figure 29 explanation is according to the DSC curve of the crystallization sitagliptin fumarate of embodiment 22 preparations.

Figure 30 explanation is according to the TGA curve of the crystallization sitagliptin fumarate of embodiment 22 preparations.

Figure 31 explanation is according to the Lactated PXRD figure of the crystallization sitagliptin of embodiment 23 preparations.

Figure 32 explanation is according to the Lactated DSC curve of crystallization sitagliptin of embodiment 23 preparations.

Figure 33 explanation is according to the Lactated TGA curve of crystallization sitagliptin of embodiment 23 preparations.

Describe in detail

All percentage used herein and ratio be with the weighing scale of total composition, and all are measured all under 25 ℃ and normal pressure and carry out, unless otherwise. All temperature in degree centigrade, unless otherwise. The present invention can comprise (open) component of the present invention and herein described other compositions or key element.

As used in this article, " comprising " refers on described key element or their structure or the equivalent on the function, adds not any other key elements of narration. Term " has " and " comprising " also should to be interpreted as be open, unless context has other prompting.

All scopes as herein described comprise end points, comprise those of scope between two values of narration.

Term such as " pact ", " usually ", " basically " etc. should be interpreted as so that described term or value are not absolute, but not covering (read on) prior art for modifying term or value. This type of term is defined by the term of linguistic context and their modifications, understands because those terms are those skilled in the art. This comprises experimental error, technical error and instrument error for the expection of the given technology of measuring certain value at least.

By with reference to " basically " collection of illustrative plates, wave spectrum or other graphical datas as shown in FIG., or by one or more data points, this paper can relate to material, in this case such as salt and its crystal form, solvate or the optical isomer of sitagliptin. By " basically " that use in such background, the reader can understand, because many factors known to those skilled in the art, collection of illustrative plates, spectrum and other graphical datas can change aspect position, relative intensity and/or value. For example, in crystallography and powder x-ray diffraction field, because (without limitation) this variation of peak position or the relative intensity aspect at one or more peaks can take place in the method for used instrument, sample preparation rules, preferably packing and orientation, radiation source, operator error, data acquisition and length etc. Yet, the image that the salt of the figure that those of ordinary skill in the art should be able to be more herein and (in this case) sitagliptin of unknown form produces, and determine its identity as disclosed herein and claimed a kind of form. Also be like this for the other technologies that may report herein.

In addition, in the quoted figures part, allow and the literature comprises and considers that selection defines the data point of any amount shown in the accompanying drawing of crystal form, salt or optical isomer uniquely.

When identifying molecule or other material for " pure " herein, this is often referred to (unless otherwise noted) described material is 99% pure or purer, and this purity is to be measured by the conventional method in this area such as high performance liquid chromatography (HPLC) or optical method. Usually, this relates to the purity about unwanted residual solvent, byproduct of reaction, impurity and unreacted raw material. In the situation of stereoisomer, " pure " also refers to 99% a kind of enantiomer or diastereomer, depends on the circumstances. " substantially pure " is identical with " pure " indication, but under be limited to about 98% or purer, similarly, " basically pure " is identical with " pure " indication, but under be limited to about 95% pure.

As used in this article, term " salt of sitagliptin ", " sitagliptin salt " and other similar phrases comprise stereoisomer, racemate, enantiomer of its crystallization and noncrystalline form, solvate, hydrate, single or form of mixtures etc.

(i) randomly in the presence of solvent, make the 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl) butyl) of formula VI-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazol [4,3-a] pyrazine

With reagent reacting, with 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl) but-2-ene base) that formula V is provided-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazol [4,3-a] pyrazine;

(ii) make the compound of formula V be converted into the 7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl) butyl) of formula IV-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazol [4,3-a] pyrazine;

(iii) with the compound of agent treatment formula IV, with the diastereoisomeric salt of sitagliptin that formula III is provided;

Wherein X is the reagent for the preparation of described diastereoisomeric salt;

(iv) diastereoisomeric salt of the described sitagliptin of separation;

(v) diastereoisomeric salt of usefulness acid or the described sitagliptin of alkali treatment is to provide the Januvia free base of formula II;

With

(vi) randomly use the described Januvia free base of acid treatment, with the acid-addition salts of sitagliptin that formula I is provided

Wherein Y is an acid group.

Step (i) comprises that the compound that randomly makes formula VI in solvent and reagent react are to provide the compound of formula V.

Suitable reagent includes but not limited to the ammonia source, such as ammonium chloride, brometo de amonio, ammonium iodide, volatile salt, ammonium formiate, ammonium acetate, methane amide, with the ammonium formiate of methanolic ammonia solution or the combination of cholamine solution, with the ammonium formiate of ammonia aqueous isopropanol combination, with the ammonium formiate of ammoniacal liquor combination, with the ammonium formiate of formic acid combination, with the methane amide of formic acid combination, with the methane amide of formic acid and the combination of ammonia aqueous isopropanol, with the methane amide of formic acid and methanolic ammonia solution combination, with formic acid and the methane amide of ammoniacal liquor combination or their mixture.For example, described ammonia source can be the ammonium acetate with the ammoniacal liquor combination.

Spendable suitable solvent includes but not limited to alcohols, such as methyl alcohol, ethanol, Virahol, propyl carbinol etc.; Nitrile is such as acetonitrile, propionitrile etc.; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone, positive butanone etc.; Halogenated solvent is such as methylene dichloride, ethylene dichloride, chloroform etc.; The ester class is such as ethyl acetate, n-propyl acetate and isopropyl acetate etc.; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane, hexanaphthene etc.; Ethers, such as 1,4-dioxane, tetrahydrofuran (THF) etc.; Sprotic polar solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N,N-DIMETHYLACETAMIDE (DMA); Water; Or their mixture.

The suitable temp of the reaction of step (i) can be less than about 150 ℃ or less than about 120 ℃ or less than about 80 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

Step comprises that (ii) the compound of formula V is converted into the compound of formula IV.

The suitable reagent that can be used for described conversion includes but not limited to that sodium borohydride, lithium aluminum hydride, vitride, sodium cyanoborohydride, carbon carry palladium, draw Buddhist nun's nickel and platinum oxide or other suitable reagent arbitrarily.For example, described reagent can be the cyano group sodium borohydride.

Spendable suitable solvent includes but not limited to alcohols, such as methyl alcohol, ethanol, Virahol, propyl carbinol etc.; Nitrile is such as acetonitrile, propionitrile etc.; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone, positive butanone etc.; Halogenated solvent is such as methylene dichloride, ethylene dichloride, chloroform etc.; The ester class is such as ethyl acetate, n-propyl acetate, isopropyl acetate etc.; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane, hexanaphthene etc.; Ethers, such as 1,4-dioxane, tetrahydrofuran (THF) etc.; Sprotic polar solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N,N-DIMETHYLACETAMIDE (DMA); Water; Or their mixture.

The suitable temp of step reaction (ii) can be less than about 250 ℃ or less than about 200 ℃ or less than about 150 ℃ or less than about 100 ℃ or less than about 80 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

This reaction can be carried out from about 30 minutes to about 10 hours or the longer any required time period.

Step (iii) comprises with the compound of the agent treated formula IV diastereoisomeric salt with sitagliptin that formula III is provided.

Operable suitable reagent includes but not limited to: S-(+)-mandelic acid, R-(-)-mandelic acid, (1S)-(+)-camphor-10-sulfonic acid, (1R)-(-)-camphor-10-sulfonic acid, L MALIC ACID, the D-oxysuccinic acid, the L-toxilic acid, the D-toxilic acid, (-)-naproxen, (+)-naproxen, (-)-to the isobutylphenyl isopropyl acid, (+)-to the isobutylphenyl isopropyl acid, (1R)-(+)-3-bromocamphor-10-sulfonic acid, (1S)-(-)-3-bromocamphor-10-sulfonic acid, L-(+)-tartrate, D-(-)-tartrate, (+)-dibenzoyl-D-tartrate, (-)-dibenzoyl-L-tartrate, (+)-di-p-tolyl-D-tartrate, (-)-di-p-tolyl-L-tartrate, L-(-)-Pyrrolidonecarboxylic acid, L-(+)-Pyrrolidonecarboxylic acid, (-)-lactic acid, L (+)-lactic acid, L-Methionin, D-Methionin, with their mixture.For example, described reagent can be (-)-di-p-tolyl-L-tartrate.

The suitable temp of step reaction (iii) can be less than about 150 ℃ or less than about 120 ℃ or less than about 80 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

This reaction can be carried out from about 30 minutes to about 30 hours or the longer any required time period.

Step (iv) comprises the diastereoisomeric salt of the sitagliptin that separates formula III.

The diastereoisomeric salt that step forms in (iii) can comprise decant, centrifugal, gravity filtration, suction filtration or as known in the artly is used to reclaim the solid other technologies and reclaims by ordinary method.The solid that reclaims can further be dried.Can be under atmospheric pressure or under reduced pressure use pan dryer, vacuum drying oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer etc. to carry out drying suitably.Can less than about 150 ℃, less than about 120 ℃, less than about 100 ℃, less than about 60 ℃, less than about 40 ℃ temperature or arbitrarily under other suitable temperature, at normal atmosphere or under reduced pressure, exist or do not exist and carry out drying under inert atmosphere such as nitrogen, argon gas, neon or the helium.Described drying can be carried out for example about 1 to about 15 hours or the longer any required time period, to reach required quality product.

The diastereoisomeric salt of formula III can come purifying with method as known in the art.For example, the diastereoisomeric salt of formula III can come purifying by precipitation in suitable solvent or preparation slurry.Can use such as crystalline method (in the concentrated solution of described diastereoisomeric salt, adding anti-solvent) or other suitable methods arbitrarily as known in the art and realize precipitation.

Step (comprises that v) diastereoisomeric salt with acid or alkaline purification formula III is to provide the Januvia free base of formula II.

The suitable alkali that can be used to handle the diastereoisomeric salt of formula II includes but not limited to: mineral alkali, such as sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide, sodium tert-butoxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc., use individually or as their aqueous solution; Organic bases is such as triethylamine, pyridine, N-methylmorpholine, Diisopropylamine, diisopropylethylamine etc.; Resin is such as ion exchange resin; With their mixture.

The suitable acid that can be used to handle the diastereoisomeric salt of formula II includes but not limited to: mineral acid, such as spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc.; Organic acid is such as acetate, propionic acid, butyric acid etc.; With their mixture.

Can be used for step (suitable solvent v) includes but not limited to: alcohols, such as, ketone, such as methyl iso-butyl ketone (MIBK), methyl ethyl ketone, positive butanone etc.; Halogenated solvent is such as methylene dichloride, ethylene dichloride, chloroform etc.; The ester class is such as ethyl acetate, n-propyl acetate, isopropyl acetate etc.; Hydrocarbon solvent is such as toluene, dimethylbenzene, hexanaphthene etc.; Ethers, such as 1,4-dioxane, tetrahydrofuran (THF) etc.; With their mixture.

(suitable temperature v) can be less than about 150 ℃ or less than about 120 ℃ or less than about 80 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily for step.

(the suitable time of reaction v) can be about 30 minutes to about 20 hours or longer to step, to reach required receipts and quality.

Step (vi) comprises randomly with the acid salt of acid treatment Januvia free base with sitagliptin that formula I is provided.

(suitable acid vi) includes but not limited to phosphoric acid, spirit of salt, oxalic acid, Hydrogen bromide, acetate, formic acid, citric acid etc. to be used for step.

Also consideration makes the acid salt of the sitagliptin of formula I be converted into Januvia free base.

For example, can handle Januvia free base so that the sitagliptin phosphoric acid salt of formula (I ') to be provided with phosphoric acid.For this reaction, the molar equivalent of spendable phosphoric acid can be about 0.5 to about 2.0 molar equivalents

(for Januvia free base).

But the drying step (acid salt of the sitagliptin of the formula I that obtains vi).Can be under atmospheric pressure or under reduced pressure, in pan dryer, vacuum drying oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer etc., carry out drying.Described drying can be less than about 100 ℃ or less than about 90 ℃ or less than about 60 ℃ or less than about 50 ℃ temperature or arbitrarily under other suitable temperature, at normal atmosphere or under reduced pressure carry out.This can carry out described drying about 1 hour to 20 hours or the longer any required time.

Randomly, the salt of described sitagliptin can come purifying with method as known in the art.For example, can take the salt of the described sitagliptin of purifying by precipitation in suitable solvent or preparation slurry.Described precipitation can realize by crystallization (by adding anti-solvent) or other suitable methods arbitrarily as known in the art.

The present invention includes the stereoselective method of preparation sitagliptin, at least one in said method comprising the steps of:

(i) make 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7 of formula VI, 8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine:

Formula VI

Chiral reagent reaction with formula VII:

Formula VII,

Wherein R is C ₁-C ₄Alkyl is with the compound of preparation formula VIII;

Formula VIII

(ii) the compound of formula VIII is converted into the compound of formula IX;

Formula IX

(iii) use acid or alkali or catalyzer that the compound of formula VIII is transformed, so that the Januvia free base of formula II to be provided; With

Formula II

(vi) randomly with the acid salt of the described Januvia free base of acid treatment with sitagliptin that formula I is provided,

Wherein Y is an acid group.

Step (i) comprises the chirality enamine of the chipal compounds reaction of the compound that makes formula VI and formula VII with preparation formula VIII.

For example, described chiral reagent can be (R)-1-phenyl-ethyl amine.

For the reaction of step (i), the molar equivalent of the chipal compounds of formula VII can be about 1.0 to about 2.0 molar equivalents (for the compound of formula VI).

The reaction of step (i) can be carried out in solvent.Spendable solvent includes but not limited to: alcohols, such as methyl alcohol, ethanol, Virahol and propyl carbinol; Organic acid is such as acetate and propionic acid; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone and positive butanone; Halogenated solvent is such as methylene dichloride, ethylene dichloride and chloroform; The ester class is such as ethyl acetate, n-propyl acetate and isopropyl acetate; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane and hexanaphthene; Ethers, such as 1,4-dioxane and tetrahydrofuran (THF); Organic acid is such as acetate, propionic acid etc.; With their mixture.

The suitable time of the reaction of step (i) can be about 30 minutes to about 10 hours or longer.

Step comprises that (ii) the compound that makes formula VIII is converted into the compound of formula IX.

Described conversion can realize by including but not limited to the reductive method.Can be at catalyzer such as platinum oxide (PtO ₂) existence under reduce.The molar equivalent of reducing catalyst can be about 0.05 to about 1.0 molar equivalents (for the compound of formula VIII).

Can be used for step solvent (ii) and include but not limited to alcohols, such as methyl alcohol, ethanol, Virahol and propyl carbinol; Organic acid is such as acetate and propionic acid; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone and positive butanone; Halogenated solvent is such as methylene dichloride, ethylene dichloride and chloroform; The ester class is such as ethyl acetate, n-propyl acetate and isopropyl acetate; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane and hexanaphthene; Ethers, such as 1,4-dioxane and tetrahydrofuran (THF); Sprotic polar organic solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) and N,N-DIMETHYLACETAMIDE (DMA); Or their mixture.

The suitable temp of step reaction (ii) can be less than about 200 ℃ or less than about 150 ℃ or less than about 100 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

The suitable time of step reaction (ii) can be about 30 minutes to about 10 hours or longer.

Step comprises that (iii) the compound that uses acid or alkali or catalyzer to make formula IX transforms, so that the Januvia free base of formula II to be provided.

Step conversion (iii) can realize by technology as known in the art.For example, can catalyzer such as carbon carry palladium, carbon carry nickel and carbon carry palladium hydroxide in the presence of, come performing step conversion (iii) by hydrogenation.

Can be used for step solvent (iii) and include but not limited to alcohols, such as methyl alcohol, ethanol, Virahol and propyl carbinol; Organic acid is such as acetate and propionic acid; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone and positive butanone; Halogenated solvent is such as methylene dichloride, ethylene dichloride and chloroform; The ester class is such as ethyl acetate, n-propyl acetate and isopropyl acetate; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane and hexanaphthene; Ethers, such as 1,4-dioxane and tetrahydrofuran (THF); Sprotic polar organic solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) and N,N-DIMETHYLACETAMIDE (DMA); Or their mixture.

Step (iv) comprises randomly with the Januvia free base of the acid treatment formula II acid salt with sitagliptin that formula I is provided.

Be used for step suitable acid (iv) and include but not limited to phosphoric acid, spirit of salt, oxalic acid, Hydrogen bromide, acetate, formic acid, citric acid etc.

For example, can handle Januvia free base so that the sitagliptin phosphoric acid salt of formula I ' to be provided with phosphoric acid.For this reaction, the molar equivalent of spendable phosphoric acid can be about 0.5 to about 2.0 molar equivalents) (for Januvia free base).

But the drying step (acid salt of the sitagliptin of the formula I that obtains vi).Can under atmospheric pressure or under reduced pressure in pan dryer, vacuum drying oven, hot air drying cabinet, fluidized bed dryer, spin flash dryer, flash dryer etc., carry out drying.Described drying can be less than about 100 ℃ or less than about 90 ℃ or less than about 60 ℃ or less than about 50 ℃ temperature or arbitrarily under other suitable temperature, at normal atmosphere or under reduced pressure carry out.This can carry out described drying about 1 hour to 20 hours or the longer any required time.

Impurity according to Januvia free base and its pharmacy acceptable salt of the method described in the application preparation is substantially free of method or structurally associated this means that described Januvia free base or its pharmacy acceptable salt comprise less than about 0.5 weight % or less than about 0.3 weight % or less than about 0.2 weight % or less than about 0.1 weight % or less than its corresponding method of about 0.05 weight % or the impurity of structurally associated.

The present invention includes the method for the compound of preparation formula VI, at least one in said method comprising the steps of:

(i) 1, under the existence of 1-carbonyl dimidazoles, make 2,4 of formula XIII, 2 of 5-trifluorophenyl acetate and formula XII, 2-dimethyl-1,3-dioxane-4,6-diketone (acid of plum clock (meldrums acid)) reaction,

Formula XIII formula XII

With the 5-(1-hydroxyl-2-(2,4, the 5-trifluorophenyl) ethylidene)-2 that formula XI is provided, 2-dimethyl-1,3-dioxane-4,6-diketone;

Formula XI

With

(ii) in the presence of diisopropylethylamine, make the compound of formula XI and the 3-trifluoromethyl-5,6,7 of formula X, 8-tetrahydrochysene-1,2, the reaction of 4-triazolo [4,3-a] pyrazine hydrochloride,

Formula X

So that the compound of formula VI to be provided.

Step (i) comprises 2,4 of formula XIII, 2 of 5-trifluorophenyl acetate and formula XII, 2-dimethyl-1,3-dioxane-4, the condensation of 6-diketone (acid of plum clock).

The molar equivalent that can be used for the plum clock acid in the step (i) can be less than about 2.0 or less than about 3.0 or less than about 5.0 molar equivalents (for the compound of formula XIII).

The alkali that can be used for step (i) includes but not limited to: organic bases, such as triethylamine, diisopropylethylamine, pyridine, imidazoles, N-methylmorpholine, sodium methylate, diisopropylamine, 1,1-carbonyl dimidazoles etc.; Mineral alkali is such as yellow soda ash, salt of wormwood, sodium bicarbonate and saleratus; Or their mixture.

The organic solvent that can be used for step (i) includes but not limited to: alcohols, such as methyl alcohol, ethanol, Virahol and propyl carbinol etc.; Organic acid is such as acetate, propionic acid etc.; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone and positive butanone etc.; Halogenated solvent is such as methylene dichloride, ethylene dichloride, chloroform etc.; The ester class is such as ethyl acetate, n-propyl acetate, isopropyl acetate etc.; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane, hexanaphthene etc.; Ethers, such as 1,4-dioxane, tetrahydrofuran (THF) etc.; Sprotic polar solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) and N,N-DIMETHYLACETAMIDE (DMF); Water; With their mixture.

The suitable temp of step reaction (ii) can be less than about 120 ℃ or less than about 100 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

Step (ii) comprises the 3-trifluoromethyl-5,6 by compound that makes formula XI in organic solvent in the presence of diisopropylethylamine and formula X, 7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] the pyrazine hydrochloride reacts so that the compound of formula VI to be provided, and comes the compound of preparation formula VI.

Can by for example herein reference example 1 method or as United States Patent (USP) 7,326, disclosed method is come the 3-trifluoromethyl-5,6 of preparation formula X in 708,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine hydrochloride, described patent is all incorporated herein by reference with it.

The 3-trifluoromethyl-5,6,7 of formula X, 8-tetrahydrochysene-1,2, the molar equivalent of 4-triazole [4,3-a] pyrazine hydrochloride can be less than about 3.0 or less than about 2.0 or less than about 1.0 molar equivalents (for the compound of formula XI).

The molar equivalent of diisopropylethylamine can be less than about 3.0 or less than about 2.0 or less than about 1.0 molar equivalents (for the compound of formula XI).

The suitable temp of step reaction (ii) can be less than about 120 ℃ or less than about 80 ℃ or less than about 60 ℃ or other suitable temperature arbitrarily.

Method of the present invention can be used for the anhydrous crystal sitagliptin dihydrogen phosphate (hereinafter being also referred to as form A) of preparation formula I '.

Formula I '

Form A can also by its about 4.58,9.23,12.24,13.88,18.23,23.63,24.24 and 26.68 ± 0.2 the degree diffraction angle 2 θ the time the XPRD characteristic peak characterize.

The present invention also comprises the method for preparing form A, and described method is included in water-content less than the step of handling Januvia free base in about 6% the solvent with phosphoric acid.

The molar equivalent of phosphoric acid can be less than about 2.0 or less than about 1.0 or less than about 0.5 molar equivalent (for Januvia free base).Described solvent can be that water concentration in described solvent is less than about 6% aqueous isopropanol.

Januvia free base can be dissolved in the suitable solvent, can in this solvent, add phosphoric acid.Can be under higher temperature all according to appointment 70 ℃ stir contents.Described content can be cooled to about 30 ℃.Can or as known in the artly be used to reclaim the solid other technologies and separate separated solid by routine techniques such as decant, centrifugal, gravity filtration, suction filtration.Can randomly dry products therefrom.Can in pan dryer, vacuum drying oven, hot air drying cabinet, fluidized bed dryer, spin flash dryer, flash dryer etc., carry out drying.Described drying can be less than about 100 ℃ or less than about 90 ℃ or less than about 60 ℃ or arbitrarily under other suitable temperature, at normal atmosphere or under reduced pressure carry out.This can carry out described drying about 1 hour to 20 hours or the longer any required time.

Except form A, the present invention includes vitriol, hydrobromate, mesylate, acetate, benzoate, oxalate, succinate, amygdalate, fumarate and the lactic acid salt of sitagliptin, these salt can be crystallized form and can prepare by method of the present invention.

For example, be provided at the crystallization sitagliptin vitriol that about 4.63,14.06,14.20,15.30,17.98,18.23,18.79,19.23,21.95,23.23,26.29 and 26.73 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin vitriol can characterize by as shown in Figure 4 PXRD figure basically.Crystallization sitagliptin vitriol can also characterize by the DSC endotherm(ic)peak about 192 ℃ the time.This crystallization sitagliptin vitriol can characterize by as shown in Figure 5 DSC thermogram basically.This crystallization sitagliptin vitriol can also characterize by about 0.0029% TGA weight loss.This crystallization sitagliptin vitriol can characterize by as shown in Figure 6 TGA curve basically.

For example, be provided at the crystallization sitagliptin hydrobromate that about 5.92,6.81,13.45,17.53,21.88,22.67,24.39,25.03 and 26.41 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin hydrobromate can characterize by as shown in Figure 7 PXRD figure basically.Crystallization sitagliptin hydrobromate can also characterize by the DSC endotherm(ic)peak about 137 ℃ the time.This crystallization sitagliptin hydrobromate can characterize by as shown in Figure 8 DSC thermogram basically.This crystallization sitagliptin hydrobromate can also characterize by about 4.178% TGA weight loss.This crystallization sitagliptin hydrobromate can characterize by as shown in Figure 9 TGA curve basically.

For example, be provided at the crystallization sitagliptin mesylate that about 5.25,6.32,6.62,11.42,18.01,19.14 and 23.91 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin mesylate can characterize by as shown in Figure 10 PXRD figure basically.Crystallization sitagliptin mesylate can also characterize by the DSC endotherm(ic)peak about 131 ℃ the time.This crystallization sitagliptin mesylate can characterize by as shown in Figure 11 DSC thermogram basically.This crystallization sitagliptin mesylate can also characterize by about 3.386% TGA weight loss.This crystallization sitagliptin mesylate can characterize by as shown in figure 12 TGA curve basically.

For example, be provided at the crystallization sitagliptin acetate that about 6.42,7.61,10.25,12.58,19.51,19.80,20.54,22.89,25.26 and 25.98 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin acetate can characterize by as shown in Figure 13 PXRD figure basically.Crystallization sitagliptin acetate can also characterize by the DSC endotherm(ic)peak about 144 ℃ the time.This crystallization sitagliptin acetate can characterize by as shown in Figure 14 DSC thermogram basically.This crystallization sitagliptin acetate can also characterize by about 14.16% TGA weight loss.This crystallization sitagliptin acetate can characterize by as shown in figure 15 TGA curve basically.

For example, be provided at the crystallization sitagliptin benzoate that about 7.19,7.45,18.11,18.38,19.35,20.42,21.81,22.61,24.11,24.63 and 27.51 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin benzoate can characterize by as shown in Figure 16 PXRD figure basically.Crystallization sitagliptin benzoate can also characterize by the DSC endotherm(ic)peak about 155 ℃ the time.This crystallization sitagliptin benzoate can characterize by as shown in Figure 17 DSC thermogram basically.This crystallization sitagliptin benzoate can also characterize by about 0.1163% TGA weight loss.This crystallization sitagliptin benzoate can characterize by as shown in figure 18 TGA curve basically.

For example, be provided at the crystallization sitagliptin oxalate that about 5.92,11.54,11.92,14.00,16.39,16.64,19.40,22.21,24.00,28.11 and 28.26 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin oxalate can characterize by as shown in Figure 19 PXRD figure basically.Crystallization sitagliptin oxalate can also characterize by the DSC endotherm(ic)peak about 98 ℃ the time.This crystallization sitagliptin oxalate can characterize by as shown in Figure 20 DSC thermogram basically.This crystallization sitagliptin oxalate can also characterize by about 6.245% TGA weight loss.This crystallization sitagliptin oxalate can characterize by as shown in figure 21 TGA curve basically.

For example, be provided at the crystallization sitagliptin succinate that about 13.06,13.50,15.73,17.04,17.35,17.57,20.15,24.35,25.15,25.76 and 26.35 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin succinate can characterize by as shown in Figure 19 PXRD figure basically.Crystallization sitagliptin succinate can also characterize by the DSC endotherm(ic)peak about 120 ℃ the time.This crystallization sitagliptin succinate can characterize by as shown in Figure 20 DSC thermogram basically.This crystallization sitagliptin succinate can also characterize by about 0.8623% TGA weight loss.This crystallization sitagliptin succinate can characterize by as shown in figure 21 TGA curve basically.

For example, be provided at the crystallization sitagliptin amygdalate that about 5.45,6.02,7.47,10.60,14.33,15.88,17.35,17.60,19.02,21.98,22.63 and 25.04 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin amygdalate can characterize by as shown in Figure 22 PXRD figure basically.Crystallization sitagliptin amygdalate can also characterize by the DSC endotherm(ic)peak about 169 ℃ the time.This crystallization sitagliptin amygdalate can characterize by as shown in Figure 23 DSC thermogram basically.This crystallization sitagliptin amygdalate can also characterize by about 0.149% TGA weight loss.This crystallization sitagliptin amygdalate can characterize by as shown in figure 24 TGA curve basically.

For example, be provided at the crystallization sitagliptin fumarate that about 6.19,7.09,15.93,16.87,17.12,19.09,21.87,24.15,25.26,26.00 and 26.19 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin fumarate can characterize by as shown in Figure 25 PXRD figure basically.Crystallization sitagliptin fumarate can also characterize by the DSC endotherm(ic)peak about 187 ℃ the time.This crystallization sitagliptin fumarate can characterize by as shown in Figure 26 DSC thermogram basically.This crystallization sitagliptin fumarate can also characterize by about 0.238% TGA weight loss.This crystallization sitagliptin fumarate can characterize by as shown in figure 27 TGA curve basically.

For example, be provided at the crystallization sitagliptin lactic acid salt that about 7.91,10.52,17.66,17.92,20.34,21.59,23.87,24.62 and 25.75 ± 0.2 degree 2 θ places have the PXRD characteristic peak.This crystallization sitagliptin lactic acid salt can characterize by as shown in Figure 28 PXRD figure basically.Crystallization sitagliptin lactic acid salt can also characterize by the DSC endotherm(ic)peak about 151 ℃ the time.This crystallization sitagliptin lactic acid salt can characterize by as shown in Figure 29 DSC thermogram basically.This crystallization sitagliptin lactic acid salt can also characterize by about 0.06007% TGA weight loss.This crystallization sitagliptin lactic acid salt can characterize by as shown in figure 30 TGA curve basically.

(a) provide the solution of salt in solvent of sitagliptin;

(c) crystal salt of recovery sitagliptin also randomly makes its drying.

Step (a) comprises the solution of salt in solvent that sitagliptin is provided.

The solution of the salt of described sitagliptin can obtain by for example the salt of the sitagliptin of arbitrary form being dissolved in the solvent.It also can obtain by the reaction mixture that comprises Januvia free base with acid treatment in solvent, and wherein said acid is sulfuric acid, Hydrogen bromide, methylsulfonic acid, acetate, phenylformic acid, oxalic acid, succsinic acid, mandelic acid, fumaric acid and lactic acid or their combination.

The solvent that can be used for step (a) includes but not limited to alcohols, such as methyl alcohol, ethanol, Virahol and propyl carbinol; Organic acid is such as acetate and propionic acid; Ketone is such as acetone, methyl iso-butyl ketone (MIBK), methyl ethyl ketone and positive butanone; Halogenated solvent is such as methylene dichloride, ethylene dichloride and chloroform; The ester class is such as ethyl acetate, n-propyl acetate and isopropyl acetate; Hydrocarbon solvent is such as toluene, dimethylbenzene, normal hexane, normal heptane and hexanaphthene; Ethers, such as 1,4-dioxane and tetrahydrofuran (THF); Sprotic polar organic solvent, such as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) and N,N-DIMETHYLACETAMIDE (DMA); Or their mixture.

If step (a) comprises the dissolving of the salt of sitagliptin, solvent temperature can be less than about 100 ℃ or less than about 90 ℃ or less than about 80 ℃ or less than about 60 ℃ or less than about 50 ℃ or other temperature arbitrarily so, and condition is that the stability of this compound is without prejudice and obtains clear soln.

In position under the salifiable situation of shape, the suitable reaction mass temperature of the addition of acid can be less than about 100 ℃ or less than about 90 ℃ or less than about 80 ℃ or less than about 60 ℃ or less than about 50 ℃ or other temperature arbitrarily, and condition is that the stability of compound is without prejudice and obtains clear soln.

Step (b) comprises the salt that separates described sitagliptin from the solution of step (a).

The salt that can from the solution of the salt of described sitagliptin, separate described sitagliptin by method as known in the art.The various isolation technique that can be used for reclaiming the salt of described sitagliptin include but not limited to precipitate by cooling off, concentrate, add crystal seed and adding anti-solvent; Distillation; And evaporation.If desired, can before the described solution of cooling, concentrate described solution by ordinary method such as evaporation, distillation.The concentration and the temperature of parameter such as solution or slurry can easily be determined and depend on to definite cooling temperature that complete crystallization is required and time by those skilled in the art.For crystallization is taken place, can adopt stir or thoroughly the additive method of mixed content thing such as shaking, shake etc.

In the crystalline sepn process, can make suspension keep time enough, so that reach separating fully of product with required yield and quality.This time can be about 1 hour to about 48 hours or longer.

Step (c) comprises the crystal salt that reclaims described sitagliptin and randomly makes its drying.

Then, can be by using any technology, such as by gravity or suction filtration, centrifugal, slowly evaporation or arbitrarily other suitable technique from suspension, reclaim crystalline solid.Isolating crystal like this can have the mother liquor that is closed of small proportion, and this mother liquor contains higher percentile impurity.If desired, can be with the described crystal of solvent wash washing out described mother liquor and/or impurity, and can randomly blot the wet crystal of gained.

The wet cake of gained in the drying step (c) randomly.Drying can be carried out in pan dryer, vacuum drying oven, hot air drying cabinet, fluidized bed dryer, spin flash dryer, flash dryer etc.Described drying can less than about 200 ℃, about 20 to about 80 ℃, about 30 to about 60 ℃ temperature or arbitrarily under other suitable temperature, at normal atmosphere or under reduced pressure carry out.Described drying can be carried out the required arbitrarily time up to reaching required quality product.

The present invention includes pharmaceutical composition, described pharmaceutical composition comprises sitagliptin or its pharmacy acceptable salt and one or more pharmaceutically acceptable vehicle less than any discrete impurity of about 0.1% of containing of treatment significant quantity.

Pharmaceutical composition of the present invention can be mixed with: solid oral dosage form comprises powder, granule, piller, tablet and capsule; Liquid oral dosage form comprises syrup, suspensoid, dispersion liquid and emulsion; And injectable formulation, comprise solution, dispersion agent and freeze dried composition.Snap-out release, delay that prescription can be suitable for activeconstituents discharge or adjustment release.Fast release composition can be a preparation conventional, dispersible, masticable, Orally dissolving or that melt fast.The adjustment release composition can comprise the material of hydrophilic and/or hydrophobic sustained release speed, to form matrix and/or storage storehouse system.Described pharmaceutical composition can be by direct mixing, dry granulation, wet granulation, extrude and/or round as a ball the preparation.Described pharmaceutical composition can be rendered as no dressing, film-coated, sugar coating, powder coated, enteric coating or the adjustment release dressing.

Composition of the present invention comprises one or more pharmaceutically acceptable vehicle.Can be used for pharmaceutically acceptable vehicle of the present invention includes but not limited to: thinner, such as starch, pregelatinized Starch, lactose, Solka-floc, Microcrystalline Cellulose, Lin Suanergai, tricalcium phosphate, N.F,USP MANNITOL, sorbyl alcohol, sugar etc.; Tackiness agent is such as gum arabic, guar gum, tragacanth gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, Vltra tears, pregelatinized Starch etc.; Disintegrating agent is such as starch, sodium starch glycollate, pregelatinized Starch, Crospovidone, cross-linked carboxymethyl cellulose sodium, colloid silica etc.; Lubricant is such as stearic acid, Magnesium Stearate, Zinic stearas etc.; Glidant is such as colloid silica etc.; Solubility enhancing agent or wetting toughener are such as anionic, cationic or neutral surface active agent; Mixture forms agent, such as various other cyclodextrin of level and resin; The rate of release control agent is such as hydroxypropylcellulose, Walocel MT 20.000PV, Vltra tears, ethyl cellulose, methylcellulose gum, various other methyl methacrylate of level, wax etc.Other pharmaceutically acceptable vehicle of available include but not limited to membrane-forming agent, softening agent, tinting material, seasonings, sweeting agent, viscosity intensifier, sanitas, antioxidant etc.

With reference to following examples, explain the application's some concrete aspect and embodiment in more detail, these embodiment only provide in the mode of explanation, and they should not be construed as the scope that limits the application in any way.

To be to use wavelength be 1.5418 to Bao Dao PXRD data herein

Cu Ka radiation obtain, be to use the Bruker AXS D8 Advance Powder X-ray Diffractometer to obtain.

Dsc analysis carries out on the DSC Q1000 instrument from TA Instruments, and ramp (ramp) is 10 ℃/minute, and modulating time is 60 seconds, and refining temperature is ± 1 ℃.Starting temperature is 0 ℃, and final temperature is 200 ℃.

TGA analyzes and carries out on TGA Q500 instrument, and ramp is 10 ℃/minute, until 250 ℃.

Embodiment

The 3-trifluoromethyl-5,6,7 of reference example: formula X, 8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazine hydrochloride

The preparation of steps A: N '-(2-chloracetyl) trifluoroacetyl hydrazine

Hydrazine hydrate (15g, 35 weight %) is mixed with acetonitrile (22.5mL) and be cooled to about 10 ℃.Continue 1 hour adding Trifluoroacetic Acid Ethyl Ester (23.3g).Gained solution was warmed to 20 ℃ and stir about 1 hour.Solution is cooled to 0-2 ℃.In 2 hours, in reaction soln, add 50 weight %NaOH solution (7.88g) and chloroacetyl chloride (22.2g) simultaneously.Reaction mixture was warmed to 15-18 ℃ and stir about 5 hours.Under about 30 ℃, under vacuum, steam and desolventize.In the gained crude product, add entry (50mL) and ethyl acetate (100mL).Separate organic layer and water layer, and (2 * 50mL) wash water layers with ethyl acetate.Merge organic layer, and wash with water (2 * 50mL), use (2 * 50mL) washings of 15% sodium chloride solution subsequently.The organic layer that merges is through dried over sodium sulfate.Under vacuum, steam fully and desolventize so that title compound to be provided.(yield: 98.3%)

Step B:5-trifluoromethyl-2-chloromethyl-1,3, the preparation of 4-oxadiazole

Add N '-(2-chloracetyl) trifluoroacetyl hydrazine (60g) and acetonitrile (120mL) in the round-bottomed flask and be cooled to about 0 ℃.Added phosphoryl chloride (27.1g) in this solution of clockwise in lasting about 15 minutes.Reaction mixture is heated to about 80 ℃ and stir about 28 hours.In container independently, mix isopropyl acetate (180mL) and water (180mL) and also be cooled to 0 ℃.Slowly reaction paste is added in this solution.Separate organic layer and, use 20% sodium chloride solution (180mL) washing at last with 5% sodium hydrogen carbonate solution (180mL) washing.With organic layer through dried over sodium sulfate.Under vacuum, steam fully and desolventize so that title compound to be provided.(yield: 82.2%)

The preparation of step C:N '-((Z)-piperazine-2-subunit) trifluoroacetyl hydrazine

Stir the solution of quadrol (89g) in methyl alcohol (305mL), and at about 45 minutes internal cooling to-20 ℃.In in about 90 minutes, slowly in this solution, adding 5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (79g) under-20 ℃.The gained slurry was-20 ℃ of following stir abouts 90 minutes.Add ethanol (482mL) and slurry is warmed to-5 ℃.-5 ℃ of stir abouts 2 hours, cross filter solid then and with ethanol (79mL) washing, and in about 55 ℃ of dryings so that title compound to be provided.(yield: 46.8%)

Step D:3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazine hydrochlorides (formula X)

Stir N '-((Z)-piperazine-2-subunit) trifluoroacetyl hydrazine (41g) in methyl alcohol (170mL) suspension and be heated to about 55 ℃.In reaction mixture, added hydrogenchloride (21mL) and stir about 2 hours.Solution is cooled to 20 ℃ and to wherein adding methyl tertiary butyl ether (423mL).Solution further was cooled to 0 ℃ and stir about 1 hour.Cross filter solid, with mixture (82mL) washing of ethanol and methyl tertiary butyl ether and in about 45 ℃ of dryings, so that title compound to be provided.(yield: 90.7%)

Embodiment 1:5-(1-hydroxyl-2-(2,4, the 5-trifluorophenyl) ethylidene)-2,2-dimethyl-1,3-dioxane-4, the preparation of 6-diketone (formula XI).

With 2,4,5-trifluorophenyl acetate (30g), tetrahydrofuran (THF) (360mL), about 50 ℃ 1,1-carbonyl dimidazoles (25.5g) mixes with plum clock acid (22.7g).Under identical temperature, mixture was stirred 5 hours.Then reaction mass is cooled to about 30 ℃.Added isopropyl acetate (180mL) and water (180mL) and stir about 30 minutes.With reaction mass be cooled to about 0 ℃ and use 36% aqueous hydrochloric acid with pH regulator to about 2.4.Separate organic layer, with washing of 0.1N aqueous hydrochloric acid and distillation fully.In the gained residue, add normal heptane (140mL) and isopropyl acetate (70mL) and about 0 ℃ of stir about 90 minutes at about 30 ℃.The solid of filtering separation also uses the mixture of normal heptane (20mL) and isopropyl acetate (10mL) to wash.About 50 ℃ with dry about 4 hours of wet cake so that title compound to be provided.(yield: 60.1%; The purity that HPLC analyzes: 98.0%)

Embodiment 2:7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazines (formula VI).

With 5-(1-hydroxyl-2-(2,4, the 5-trifluorophenyl) ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-diketone (10g), 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture heating up of 4-triazolo [4,3-a] pyrazine hydrochlorides (7.2g), diisopropylethylamine (4.5g) and isopropyl acetate (100mL) was to about 85 ℃ and stir about 4 hours.Then reaction mass is cooled to about 30 ℃ and water (90mL) termination reaction.Separate organic layer,, under vacuum, distill fully so that 12g to be provided title compound with 5% sodium chloride solution (3x50mL) washing.(yield: 93.3%; The purity that HPLC analyzes: 95.7%)

Embodiment 3:7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazines (formula V).

With 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture heating up of 4-triazolo [4,3-a] pyrazines (22.1g), ammonium acetate (25g), methyl alcohol (220mL) and ammoniacal liquor (22mL) was to about 55 ℃ and stir about 6 hours.Then reaction mass is cooled to about 30 ℃ and remove by filter undissolved particle.Under vacuum, distill filtrate fully.Add ethanol (25mL) in residuum, mixture was about 30 ℃ of stir abouts 30 minutes.Cross filter solid, with ethanol (5mL) washing, dry so that title compound to be provided.(yield: 75%; The purity that HPLC analyzes: 96.7%)

Embodiment 4:7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazines (formula IV).

Under about 30 ℃ with methyl alcohol (135mL), 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture stir about of the hydrogen chloride methanol solution (35mL) of 4-triazolo [4,3-a] pyrazines (13.5gm), sodium cyanoborohydride (2.5g) and pH about 4.5 5 hours.Steam fully and desolventize and in residuum, add entry (50mL).(150mL) extracts with ethyl acetate.Distill the gained organic layer fully so that title compound to be provided.(yield: 99.9%; The purity that HPLC analyzes: 92.25%)

Embodiment 5: the preparation of sitagliptin di-p-tolyl-L-tartrate.

With methyl alcohol (390mL), water (80mL), 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture stir about of 4-triazolo [4,3-a] pyrazines (13g) and di-p-tolyl-L-tartrate (13g) 24 hours.Filter out isolating solid, with ethanol (15mL) washing, in about 45 ℃ of dryings so that title compound to be provided.(yield: 66.3%; The purity that HPLC analyzes: 99.93%)

Embodiment 6: the preparation of sitagliptin phosphoric acid salt monohydrate (formula I).

Under stirring, in the mixture of ethyl acetate (10mL), water (15mL), sitagliptin di-p-tolyl-L-tartrate (0.4g), add 10% sodium hydroxide solution at about 5 ℃.Stirred this mixture about 30 minutes.Separate each layer and use ethyl acetate (10mL) aqueous layer extracted.The organic layer of distillation merging is to provide 0.2gm Januvia free base fully.

Januvia free base is dissolved in the mixture of Virahol (5mL) and water (0.2mL), to wherein adding 85% phosphoric acid (0.056g).Content is heated to about 70 ℃, kept about 30 minutes, be cooled to about 30 ℃ and stir about then 15 hours.The solid of filtering separation, with Virahol (1mL) washing, about 3 hours of about 50 ℃ of dryings so that title compound to be provided.(yield: 68%; The purity that HPLC analyzes: 99.87%; SOR:-20.7 ℃ (c=1%, Yu Shuizhong))

Embodiment 7:(Z)-and 7-(1-oxo-3 ((R)-1-phenylethyl amino)-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazines (formula VIII).

With Virahol (10mL), 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture heating up of 4-triazolo [4,3-a] pyrazines (2g) and R-1-phenyl-ethyl amine is to about 40 ℃.Added acetate (0.15mL) and stir about 5 hours.Steam fully and desolventize so that title compound to be provided.(yield: 99.7%; M/z:510 (m+1))

Embodiment 8:7-(1-oxo-3 ((R)-((R)-1-phenylethyl amino))-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the preparation of 4-triazolo [4,3-a] pyrazines (formula IX).

With tetrahydrofuran (THF) (80ml), methyl alcohol (20ml), (Z)-7-(1-oxo-3 ((R)-l-phenylethyl amino)-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, be heated to about 40 ℃ in 4-triazolo [4,3-a] pyrazines (8g) and platinum oxide (1.0g) the adding autoclave vessel and with content.Apply about 12-14kg/cm ²H ₂Press, and under identical temperature, kept this pressure about 10 hours.Then reaction mass is cooled to about 30 ℃, removes by filter catalyzer then.Under vacuum, distill filtrate fully so that 8.2gm to be provided title compound.

Embodiment 9: the preparation of sitagliptin (formula II).

With tetrahydrofuran (THF) (10ml), methyl alcohol (10ml), 7-(1-oxo-3 ((R)-((R)-1-phenylethyl amino))-4-(2,4, the 5-trifluorophenyl) butyl)-and 3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazines (2g), formic acid (2Ml), 20% palladium hydroxide carbon (0.5g) and water (2mL) add in the round-bottomed flask, and content is heated to about 60 ℃, kept about 6 hours.Then reaction mass is cooled to about 30 ℃ and filtering catalyst.Under vacuum, distill filtrate fully.In residuum, add entry (10mL) and ethyl acetate (20mL) and it is cooled to about 0 ℃.In reaction mass, add phosphoric acid (0.4g) and separate each layer.Water layer is cooled to about 0 ℃, adds 5% sodium hydroxide and reach about 12.0 up to the pH of material.Use ethyl acetate (20mL) extraction material then, distill ethyl acetate layer fully so that title compound to be provided.(yield: 79.4%)

Embodiment 10: the preparation of sitagliptin phosphoric acid salt monohydrate (formula I).

The 7-[(3R of adding formula II)-3-amino-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5,6,7,8-tetrahydrochysene-3-(trifluoromethyl)-1,2,4-triazolo [4,3-a] pyrazines (0.4g), Virahol (5mL), water (0.4mL) and phosphoric acid (0.11g), be heated to about 70 ℃, kept about 3 hours.Then reaction mass was cooled to about 30 ℃ and stir about 10 hours.The solid of filtering separation and about 45 ℃ under vacuum with about 4 hours of solid drying so that title compound to be provided.(yield: 68%; The purity that HPLC analyzes: 96.67; The purity that chirality HPLC analyzes: 99.19%; M/z:408 (m+1); SOR:-21 ℃ (c=1%, Yu Shuizhong))

Embodiment 11: the preparation of sitagliptin (formula II).

At about 10 ℃ 10% sodium hydroxide solution (10mL) joined 7-(1-oxo-3-((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, in the mixture of 4-triazolo [4,3-a] pyrazine di-p-tolyl-L-tartrate (8.5g) and ethyl acetate (30mL).Under identical temperature, stir this mixture up to the clarification that becomes.Separate each layer then and distill organic layer fully.Adding Virahol (5mL) also stirs up to solution and clarifies.In solution, added normal heptane (25mL) and stir about 9 hours.Cross filter solid, with normal heptane (5mL) washing, drying under reduced pressure is to provide title compound.(yield: 99.5%)

Embodiment 12: the preparation of sitagliptin phosphoric acid salt monohydrate (formula I).

With 7-(1-oxo-3-((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2, the mixture heating up of 4-triazolo [4,3-a] pyrazines (2gm), water (2mL), Virahol (4mL) and 85% phosphoric acid (0.567g) is to about 75 ℃ and stir up to the mixture clarification that becomes.Then this mixture was cooled to about 68 ℃ and stir about 2 hours.Further it is cooled to about 4 ℃ and stir and to spend the night.Added Virahol (14mL) and stir about 1 hour.Cross filter solid, with the mixture washing of Virahol (4.5mL) and water (0.5mL), so that title compound to be provided.(yield: 93.38%; The purity that HPLC analyzes: 99.96%)

Embodiment 13: the preparation of anhydrous crystal sitagliptin dihydrogen phosphate (form A)

Under stirring, in the mixture of ethyl acetate (25mL), water (20mL) and sitagliptin di-p-tolyl-L-tartrate (8.0g), add 10% sodium hydroxide solution (15mL) at about 5 ℃.Stirred this mixture about 30 minutes.Separate each layer and use ethyl acetate (50mL) aqueous layer extracted.The organic layer of distillation merging is to provide 4.1g Januvia free base fully.

Januvia free base is dissolved in the mixture of Virahol (80mL) and water (4.0mL).Add 85% phosphoric acid (1.13g).Content is heated to about 70 ℃, kept about 30 minutes, be cooled to about 30 ℃ and stir about then 15 hours.The solid of filtering separation, with Virahol (1mL) washing, about 3 hours of about 50 ℃ of dryings so that title compound to be provided.(yield: 85.6%; The purity that HPLC analyzes: 99.96%)

Embodiment 14: the preparation of sitagliptin vitriol.

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 15 minutes, to obtain clear soln.Add sulfuric acid (1.2g) and made reaction mixture refluxed about 1 hour.Reaction mixture was cooled to about 30 ℃ and stir about 22 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 1.5 hours so that title compound to be provided at about 40 ℃.(output: 6.0g; MC:0.84%w/w; HPLC purity: 99.98%)

Embodiment 15: the preparation of sitagliptin hydrobromate

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 30 minutes, to obtain clear soln.Add Hydrogen bromide (2.1g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 22 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 1.25 hours so that title compound to be provided at about 35 ℃.(output: 4.0g; MC:2.40%w/w; HPLC purity: 99.70%)

Embodiment 16: the preparation of sitagliptin mesylate

Sitagliptin (5g) and Virahol (50mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 20 minutes, to obtain clear soln.Add methylsulfonic acid (1.11g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 16 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 2.5 hours so that title compound to be provided at about 45 ℃.(output: 6.0g; MC:0.97%w/w; HPLC purity: 99.92%)

Embodiment 17: the preparation of sitagliptin acetate

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 20 minutes, to obtain clear soln.Add acetate (0.73g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 8.5 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 3.5 hours so that title compound to be provided at about 30 ℃.(output: 5.6g; MC:0.79%w/w; HPLC purity: 99.81%)

Embodiment 18: the preparation of sitagliptin benzoate

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 20 minutes, to obtain clear soln.Add phenylformic acid (1.49g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 21.5 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 1.5 hours so that title compound to be provided at about 40 ℃.(output: 5.9g; MC:0.80%w/w; HPLC purity: 99.82%)

Embodiment 19: the preparation of sitagliptin oxalate

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 30 minutes, to obtain clear soln.Add and be dissolved in the oxalic acid (1.54g) in the water (5mL) and made reaction mixture refluxed about 1 hour.Reaction mixture was cooled to about 30 ℃ and stir about 22 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 2.5 hours so that title compound to be provided at about 40 ℃.(output: 5.8g; MC:6.54%w/w; HPLC purity: 99.95%)

Embodiment 20: the preparation of sitagliptin succinate

Sitagliptin (5g) and Virahol (50mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 30 minutes, to obtain clear soln.Add succsinic acid (1.44g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 23 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 3 hours so that title compound to be provided at about 50 ℃.(output: 4.0g; MC:1.79%w/w; HPLC purity: 99.72%)

Embodiment 21: the preparation of sitagliptin amygdalate

Sitagliptin (4g) and Virahol (60mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 30 minutes, to obtain clear soln.Add mandelic acid (1.49g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 21.5 hours.The solid of filtering separation with Virahol (4mL) washing, under reduced pressure is dried about 2 hours so that title compound to be provided at about 45 ℃.(output: 4.4g; MC:0.51%w/w; HPLC purity: 99.56%)

Embodiment 22: the preparation of sitagliptin fumarate

Sitagliptin (4g) and Virahol (60mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 30 minutes, to obtain clear soln.Add fumaric acid (1.14g) and made reaction mixture refluxed about 2 hours.Reaction mixture was cooled to about 30 ℃ and stir about 21 hours.The solid of filtering separation with Virahol (4mL) washing, under reduced pressure is dried about 2 hours so that title compound to be provided at about 45 ℃.(output: 4.0g; MC:1.05%w/w; HPLC purity: 99.47%)

Embodiment 23: the Lactated preparation of sitagliptin

Sitagliptin (5g) and Virahol (75mL) are added in the round-bottomed flask, mixture heating up to about 80 ℃, was kept about 20 minutes, to obtain clear soln.Add lactic acid (1.10g) and made reaction mixture refluxed about 1.5 hours.Reaction mixture was cooled to about 30 ℃ and stir about 8.5 hours.The solid of filtering separation with Virahol (5mL) washing, under reduced pressure is dried about 2 hours so that title compound to be provided at about 45 ℃.(output: 4.0g; MC:0.62%w/w; HPLC purity: 99.75%)

Claims

1. prepare the method for sitagliptin or its salt, said method comprising the steps of:

(1) makes 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4, the 3-a] pyrazine and first reagent react, so that 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5 to be provided, 6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine;

(2) make described 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) but-2-ene base)-3-trifluoromethyl-5 with second reagent, 6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine is converted into 7-(1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine;

(3) with the described 7-of the 3rd agent treated (1-oxo-3-amino-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine, so that 7-(1-oxo-3 ((R)-amino)-4-(2,4, the 5-trifluorophenyl) butyl)-3-(trifluoromethyl)-5 to be provided, 6,7,8-tetrahydrochysene-1,2, the diastereoisomeric salt of 4-triazolo [4,3-a] pyrazine;

(4) separate described diastereoisomeric salt; With

(5) with acid or the described diastereoisomeric salt of alkaline purification so that Januvia free base to be provided.

2. the process of claim 1 wherein described first reagent be ammonium chloride, brometo de amonio, ammonium iodide, volatile salt, ammonium formiate, ammonium acetate, methane amide, with the ammonium formiate of methanolic ammonia solution or the combination of cholamine solution, with the ammonium formiate of ammonia aqueous isopropanol combination, with the ammonium formiate of ammoniacal liquor combination, with the ammonium formiate of formic acid combination, with the methane amide of formic acid combination, with the methane amide of formic acid and the combination of ammonia aqueous isopropanol, with the methane amide of formic acid and methanolic ammonia solution combination, with formic acid and the methane amide of ammoniacal liquor combination or their mixture.

3. claim 1 or 2 method, wherein said second reagent are that sodium borohydride, lithium aluminum hydride, vitride, sodium cyanoborohydride, carbon carry palladium, draw Buddhist nun's nickel, platinum oxide or zinc-acetate.

4. any one method among the claim 1-3, wherein said the 3rd reagent is S-(+)-mandelic acid, R-(-)-mandelic acid, (1S)-(+)-camphor-10-sulfonic acid, (1R)-(-)-camphor-10-sulfonic acid, L MALIC ACID, the D-oxysuccinic acid, the L-toxilic acid, the D-toxilic acid, (-)-naproxen, (+)-naproxen, (-)-to the isobutylphenyl isopropyl acid, (+)-to the isobutylphenyl isopropyl acid, (1R)-(+)-3-bromocamphor-10-sulfonic acid, (1S)-(-)-3-bromocamphor-10-sulfonic acid, L-(+)-tartrate, D-(-)-tartrate, (+)-dibenzoyl-D-tartrate, (-)-dibenzoyl-L-tartrate, (+)-di-p-tolyl-D-tartrate, (-)-di-p-tolyl-L-tartrate, L-(-)-Pyrrolidonecarboxylic acid, L-(+)-Pyrrolidonecarboxylic acid, (-)-lactic acid, L (+)-lactic acid, L-Methionin, D-Methionin, or their mixture.

5. any one method among the claim 1-4, described method also comprises the step that Januvia free base is converted into the acid salt of sitagliptin, wherein said acid is phosphoric acid, hydrochloric acid, oxalic acid, Hydrogen bromide, acetate, formic acid or citric acid.

6. the method for claim 5, the acid salt of wherein said sitagliptin is the sitagliptin dihydrogen phosphate.

7. prepare the Stereoselective method of sitagliptin or its salt, said method comprising the steps of:

(i) make 7-(1,3-dioxo-4-(2,4, the 5-trifluorophenyl) butyl)-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazolo [4,3-a] pyrazine and chiral reagent reaction are with the compound of preparation formula VIII;

Wherein R is C ₁-C ₄Alkyl;

(ii) the compound of formula VIII is converted into the compound of formula IX

Wherein R as above defines;

8. the method for claim 7, wherein said chiral reagent is (R)-1-phenyl-ethyl amine.

9. claim 1 or 7 method, wherein said sitagliptin or its salt are the crystallization sitagliptin vitriol that has the PXRD characteristic peak at about 4.63,14.06,14.20,15.30,17.98,18.23,18.79,19.23,21.95,23.23,26.29 and 26.73 ± 0.2 degree 2 θ places.

10. claim 1 or 7 method, wherein said sitagliptin or its salt are the crystallization sitagliptin hydrobromates that has the PXRD characteristic peak at about 5.92,6.81,13.45,17.53,21.88,22.67,24.39,25.03 and 26.41 ± 0.2 degree 2 θ places.

11. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin mesylates that has the PXRD characteristic peak at about 5.25,6.32,6.62,11.42,18.01,19.14 and 23.91 ± 0.2 degree 2 θ places.

12. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin acetates that has the PXRD characteristic peak at about 6.42,7.61,10.25,12.58,19.51,19.80,20.54,22.89,25.26 and 25.98 ± 0.2 degree 2 θ places.

13. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin benzoates that has the PXRD characteristic peak at about 7.19,7.45,18.11,18.38,19.35,20.42,21.81,22.61,24.11,24.63 and 27.51 ± 0.2 degree 2 θ places.

14. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin oxalate that has the PXRD characteristic peak at about 5.92,11.54,11.92,14.00,16.39,16.64,19.40,22.21,24.00,28.11 and 28.26 ± 0.2 degree 2 θ places.

15. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin succinates that has the PXRD characteristic peak at about 13.06,13.50,15.73,17.04,17.35,17.57,20.15,24.35,25.15,25.76 and 26.35 ± 0.2 degree 2 θ places.

16. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin amygdalates that has the PXRD characteristic peak at about 5.45,6.02,7.47,10.60,14.33,15.88,17.35,17.60,19.02,21.98,22.63 and 25.04 ± 0.2 degree 2 θ places.

17. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin fumarates that has the PXRD characteristic peak at about 6.19,7.09,15.93,16.87,17.12,19.09,21.87,24.15,25.26,26.00 and 26.19 ± 0.2 degree 2 θ places.

18. the method for claim 1 or 7, wherein said sitagliptin or its salt are the crystallization sitagliptin lactic acid salts that has the PXRD characteristic peak at about 7.91,10.52,17.66,17.92,20.34,21.59,23.87,24.62 and 25.75 ± 0.2 degree 2 θ places.